Our research goal is to develop a new, robust therapeutic agent that seeks and destroys human neuroblastoma. Neuroblastoma is the most common cancer in infancy and children. High-risk neuroblastomas are difficult to cure even with the most aggressive of combination or multi-modal therapies. Our preliminary studies suggest the feasibility of using new protelipid nanovesicles to target and treat neuroblastomas with minimal side effects. The nanovesicle is consisted of the small fusogenic lysosomal protein saposin C (SapC) and the phospholipid dioleoylphosphatidylserine (DOPS). This stably formed SapC-DOPS nanovesicle has preferential affinity for phosphatidylserine (PS) exposed on the surface of cancer cells and neovessels. We have shown that the nanovesicles have high propensity to accumulate in neuroblastoma tumors, and induces apoptosis in the cancer cells. Upon repeated SapC-DOPS injection in neuroblastoma-bearing animals, we observed a significantly inhibitory effect on tumor growth by inducing apoptotic cancer cell death via acid sphingomyelinase-derived ceramide-mediated signaling pathways. The objective in this proposal is to determine SapC-DOPS nanovesicles for their application in treating neuroblastomas. The specific aims are to (1) determine the relationship of cell surface PS levels of human neuroblastoma cells and the targeting and cytotoxic responses to SapC-DOPS nanovesicles, (2) develop a SapC-DOPS sensitization agent that specifically promotes the PS exposure on the surface of human neuroblastoma, and (3) delineate the molecular mechanism underlying SapC-DOPS induced apoptotic cell death of human neuroblastoma via the ceramide-mediated mitochondria-centric signaling pathway. This research is innovative because SapC-DOPS nanovesicles offer a unique approach for seeking and treating neuroblastomas, as well as other tumors with cell surface exposed PS. The successfully completion of the proposed research will have a major impact on the field of cancer clinical research, since it provides a safe and broad clinical approach for cancer therapy.